Mmp-12 inhibitors

ABSTRACT

A compound of the formula (1):  
                 
 
     wherein R 1  is hydroxy and the like; R 2  is optionally substituted lower alkyl and the like; R 3  is hydrogen atom and the like; R 4  is optionally substituted arylene and the like; R 5  is —C≡C— and the like; R 6  is optionally substituted naphtyl and the like  
     its optically active substance, its prodrug, their pharmaceutically acceptable salt, or solvate thereof.

TECHNICAL FIELD

[0001] This invention relates to sulfonamide derivatives, especiallysulfonamide derivatives which selectively inhibit matrixmetalloproteinases-12.

BACKGROUND ART

[0002] An extracellular matrix, consisting of collagen, fibronectin,laminin, proteoglycan, etc., has a function to support tissues, andplays a role in propagation, differentiation, adhesion, or the like incells. Metalloproteinases which are protease having a metal ion in theactive center, especially matrix metalloproteinases (MMP), are concernedwith the degradation of the extracellular matrix. Many types of MMP,from MMP-1 (collagenase type I) to MMP-23, have been reported as enzymesworking for the growth, remodeling of tissues, etc. under usualphysiological conditions. It is reported, however, that the progressionof various kinds of diseases involving breakdown and fibrosis of tissues(e.g., osteoarthritis, rheumatoid arthritis, corneal ulceration,periodontitis, metastasis and invasion of tumor, and virus infection(HIV infection)) is related with increase of the manifestation oractivity of the above-mentioned enzyme.

[0003] Matrix metalloproteinases-12 (MMP-12) is produced from macrophageand has a character which decomposes elastin and is different from otherMMPs'. It is known that this enzyme cleaves collagen type I, collagentype IV, fibronectin, laminin and the like. It is also described inSCIENCE 1997, 277(26), 2002-2004 and Exp. Opin. Ther. Patents(1999)9(7),851-895 and the like that MMP-12 plays a role in pulmonaryemphysema. Therefore, MMP-12 is considered to be involved in thepathogenesis of chronic obstructive pulmonary disease (COPD) which ischaracterized by respiratory obstruction caused by pulmonary emphysemaor chronic bronchitis. It is suggested in Exp. Opin. Ther. Patents(1999) 9(7),851-895 and the like that MMP-12 relates to diseases ofmetastatic carcinoma, atherosclerosis and the like.

[0004] Sulfonamide derivatives having an inhibitory activity against,MMP are described in WO97/27174, WO99/04780 and the like.

[0005] No compound having an inhibitory activity against MMP-12 isknown.

DISCLOSURE OF INVENTION

[0006] The inhibition of such MMP-12 activities is considered tocontribute to the improvement and prevention of the above diseasescaused by or related to the activity. Therefore, the development ofMMP-12 inhibitors has been desired.

[0007] In the above situation, the inventors of the present inventionhave found that certain sulfonamide derivatives having a bisyclic ortricyclic condensed ring at a terminal position have a potent activityto inhibit MMP-12.

[0008] The present invention relates to:

[0009] 1) A compound of the formula (I):

[0010] wherein R¹ is NHOH, hydroxy, or lower alkyloxy;

[0011] R² is hydrogen atom, optionally substituted lower alkyl,optionally substituted aryl, optionally substituted aralkyl, optionallysubstituted heteroaryl, or optionally substituted heteroarylalkyl;

[0012] R³ is hydrogen atom, optionally substituted lower alkyl,optionally substituted aryl, optionally substituted aralkyl, optionallysubstituted heteroaryl, or optionally substituted heteroarylalkyl;

[0013] R⁴ is optionally substituted arylene, or optionally substitutedheteroarylene; R⁵ is a bond, —(CH₂)p—, —CH═CH—, —C≡C—, —CO—, —CO—NH—,—N═N—, —N(R^(A))—, —NH—CO—NH—, —NH—CO—, —O—, —S—, —SO₂—, —SO₂NH—,—SO₂—NH—N═CH—, or

[0014] a group represented by the formula:

[0015] wherein R^(A) is hydrogen atom or lower alkyl, p is 1 or 2

[0016] R⁶ is optionally substituted naphtyl, optionally substitutedisoquinolyl, optionally substituted quinolyl, optionally substituted1,3-benzodioxolyl, optionally substituted benzofuranyl, or optionallysubstituted benzothienyl, its optically active substance, its prodrug,their pharmaceutically acceptable salt, or solvate thereof.

[0017] In more detail, the invention relates to the following 2)-23).

[0018] 2) A compound of the formula (II):

[0019] wherein R¹, R², R³, R⁴ and R⁵ are as defined in 1);

[0020] R⁷ is each independently hydrogen atom, halogen, lower alkyl,cycloalkyl, lower alkenyl, lower alkynyl, lower alkyloxy, loweralkenyloxy, lower alkylthio, halo(lower)alkyl, hydroxy, carboxy, loweralkyloxycarbonyl, aminocarbonyl, acyl, nitro, cyano, or optionallysubstituted amino;

[0021] m is 0, 1, 2, or 3,

[0022] its optically active substance, its prodrug, theirpharmaceutically acceptable salt, or solvate thereof.

[0023] 3) A compound of the formula (III):

[0024] wherein R¹, R³, R⁴, and R⁵ are as defined in 1);

[0025] R⁷ and m are as defined in 2);

[0026] R⁸ is hydrogen atom, lower alkyl optionally substituted withaminocarbonyl or lower alkylthio, aryl optionally substituted withhydroxy, aralkyl optionally substituted with hydroxy, or heteroarylalkyloptionally substituted with hydroxy,

[0027] its optically active substance, its prodrug, theirpharmaceutically acceptable salt, or solvate thereof.

[0028] 4) A compound, its optically active substance, its prodrug, theirpharmaceutically acceptable salt, or solvate thereof as described in anyone of 1) to 3), wherein R¹ is hydroxy.

[0029] 5) A compound, its optically active substance, its prodrug, theirpharmaceutically acceptable salt, or solvate thereof as described in anyone of 1) to 4), wherein R² and R⁸ are hydrogen atom, lower alkyloptionally substituted with aminocarbonyl or lower alkylthio, phenyloptionally substituted with hydroxy, benzyl optionally substituted withhydroxy, or indol-3-ylmethyl optionally substituted with hydroxy.

[0030] 6) A compound, its optically active substance, its prodrug, theirpharmaceutically acceptable salt, or solvate thereof as described in anyone of 1) to 5), wherein R² and R⁸ are hydrogen atom, methyl, isopropyl,isobutyl, aminocarbonylmethyl, 2-methylthioethyl, 4-hydroxyphenyl,benzyl, 4-hydroxybenzyl, indol-3-ylmethyl, or(5-hydroxy-indol-3-yl)methyl.

[0031] 7) A compound, its optically active substance, its prodrug, theirpharmaceutically acceptable salt, or solvate thereof as described in anyone of 1) to 6), wherein R³ is hydrogen atom.

[0032] 8) A compound, its optically active substance, its prodrug, theirpharmaceutically acceptable salt, or solvate thereof as described in anyone of 1) to 7), wherein R⁴ is 1,4-phenylene or 2,5-thiophen-diyl.

[0033] 9) A compound, its optically active substance, its prodrug, theirpharmaceutically acceptable salt, or solvate thereof as described in anyone of 1) to 8), wherein R⁵ is —C≡13 C—, —CO—NH—, —NH—CO—, —O—, or

[0034] a group represented by a formula:

[0035] 10) A compound of the formula (IV):

[0036] wherein R⁹ is hydrogen atom, methyl, isopropyl, isobutyl,aminocarbonylmethyl, 2-methylthioethyl, 4-hydroxyphenyl, benzyl,4-hydroxybenzyl, indol-3-ylmethyl, or (5-hydroxy-indol-3-yl)methyl;

[0037] R¹⁰ is 1,4-phenylene or 2,5-thiophen-diyl;

[0038] R¹¹ is —C≡—C—, —CO—NH—, —NH—CO—, —O—, or

[0039] a group represented by a formula:

[0040] R¹² is each independently hydrogen atom, halogen, lower alkyl,lower alkyloxy, halo(lower)alkyl, nitro, cyano, optionally substitutedamino, or hydroxy;

[0041] m is 0, 1, 2, or 3,

[0042] its optically active substance, its prodrug, theirpharmaceutically acceptable salt, or solvate thereof.

[0043] 11) A pharmaceutical composition containing a compound of any oneof 1) to 10) as an active ingredient.

[0044] 12) A composition for inhibiting metalloproteinase containing acompound of any one of 1) to 10) as an active ingredient.

[0045] 13) A composition for inhibiting matrix metalloproteinasecontaining a compound of any one of 1) to 10) as an active ingredient.

[0046] 14) A composition for inhibiting matrix metalloproteinase-12containing a compound of any one of 1) to 10) as an active ingredient.

[0047] 15) A composition for treating or preventing chronic obstructivepulmonary disease which contains as an active ingredient a compound ofany one of 1) to 10).

[0048] 16) Use of a compound of any one of 1) to 10) for preparation ofa pharmaceutical composition for treating chronic obstructive pulmonarydisease.

[0049] 17) A method for treating a mammal, including a human, toalleviate the pathological effects of chronic obstructive pulmonarydisease, which comprises administration to said mammal of a compound asdescribed in any one of 1) to 10) in a pharmaceutically effectiveamount.

[0050] 18) A method of inhibiting MMP-12, which is characterized bycontacting a compound as described in any one of 1) to 10) with MMP-12.

[0051] 19) A pharmaceutical composition containing as an activeingredient a compound having an inhibitory activity against matrixmetalloproteinase-12.

[0052] 20) A composition for treating or preventing chronic obstructivepulmonary disease containing as an active ingredient a compound havingan inhibitory activity against matrix metalloproteinase-12.

[0053] 21) A method for treating a mammal, including a human, toalleviate the pathological effects of chronic obstructive pulmonarydisease, which comprises administration to said mammal of a compoundhaving an inhibitory activity against matrix metalloproteinase-12.

[0054] 22) Use of a compound having an inhibitory activity againstmatrix metalloproteinase-12 for preparation of a pharmaceuticalcomposition for treating chronic obstructive pulmonary disease.

[0055] 23) A method of inhibiting matrix metalloproteinase-12, which ischaracterized by contacting a compound having an inhibitory activityagainst matrix metalloproteinase-12 with matrix metalloproteinase-12.

[0056] In the present specification, the term “lower alkyl” employedalone or in combination with other terms means a straight- or branchedchain monovalent hydrocarbon group having 1 to 8 carbon atom(s).Examples of the alkyl include methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl,neo-pentyl, n-hexyl, isohexyl, n-heptyl, n-octyl and the like. C1 to C6alkyl is preferred. C1 to C3 alkyl is more preferred.

[0057] The term “lower alkenyl” employed alone or in combination withother terms in the present specification means a straight- or branchedchain monovalent hydrocarbon group having 2 to 8 carbon atoms and atleast one double bond. Examples of the alkenyl include vinyl, allyl,propenyl, crotonyl, isopentenyl, a variety of butenyl isomers and thelike. C2 to C6 alkenyl is preferred. C2 to C4 alkenyl is more preferred.

[0058] The term “lower alkynyl” used in the present specification meansa straight- or branched chain monovalent hydrocarbon group having 2 to 8carbon atoms and at least one triple bond. The alkynyl may contain (a)double bond(s). Examples of the alkynyl include ethynyl, 2-propynyl,3-butynyl, 4-pentynyl, 5-hexynyl, 6-heptynyl, 7-octynyl and the like. C2to C6 alkynyl is preferred. C2 to C4 alkynyl is more preferred.

[0059] The term “cycloalkyl ” used in the present specification includescycloalkyl group having 3 to 8 carbon atoms. Examples of cycloalkylgroup include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl and the like. C3 to C6 cycloalkyl is preferred.

[0060] In the present specification, the term “aryl” employed alone orin combination with other terms includes monocyclic or condensed ringaromatic hydrocarbons. Examples include phenyl, 1-naphtyl, 2-naphtyl,anthryl, and the like.

[0061] Preferable is phenyl as “aryl” for R².

[0062] Preferable is phenyl as “aryl” for R³.

[0063] In the present specification, the term “naphtyl” includes1-naphtyl and 2-naphtyl.

[0064] The term “aralkyl” herein used means the above-mentioned “loweralkyl” substituted with one or more above-mentioned “aryl” at anypossible position. Examples of the aralkyl are benzyl, phenylethyl(e.g., 2-phenethyl and the like), phenylpropyl (e.g., 3-phenylpropyl andthe like), naphthylmethyl (e.g., 1-naphthylmethyl and 2-naphthylmethyland the like), anthrylmethyl (e.g., 9-anthrylmethyl and the like), andthe like. Benzyl and phenylethyl are preferred.

[0065] In the present specification, the term “heteroaryl” employedalone or in combination with other terms includes a 5 to 6 memberedaromatic heterocyclic group which contains one or more hetero atomsselected from the group consisting of oxygen, sulfur, and nitrogen atomsin the ring and may be fused with cycloalkyl, aryl, non-aromaticheterocyclic group, and other heteroaryl at any possible position.Examples of the heteroaryl are pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl,3-pyrrolyl), furyl (e.g., 2-furyl, 3-furyl), thienyl (e.g., 2-thienyl3-thienyl), imidazolyl (e.g., 2- imidazotyl, 4-imidazolyl), pyrazolyl(e.g., 1-pyrazolyl, 3-pyrazolyl), isothiazolyl (e.g., 3-isothiazolyl),isoxazolyl (e.g., 3-isoxazolyl), oxazolyl (e.g., 2-oxazolyl), thiazolyl(e.g., 2-thiazolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl),pyrazinyl (e.g., 2-pyrazinyl), pyrimidinyl (e.g., 2-pyrimidinyl,4-pyrimidinyl), pyridazinyl (e.g., 3-pyridazinyl), tetrazolyl (e.g.,1H-tetrazolyl), oxadiazolyl (e.g., 1,3,4-oxadiazolyl), thiadiazolyl(e.g., 1,3,4- thiadiazolyl), indolizinyl (e.g., 2-indolizinyl,6-indolizinyl), isoindolyl (2-isoindolyl), indolyl (e.g., 1-indolyl,2-indolyl, 3-indolyl), indazolyl (e.g., 3-indazolyl), puriyl (e.g.,8-puriyl), quinolizinyl ( e.g., 2-quinolizinyl), isoquinolyl (e.g.,3-isoquinolyl), quinolyl (e.g., 2-quinolyl, 5-quinolyl), phthalazinyl(e.g., 1-phthalazinyl), naphthyridlinyl (e.g., 2-naphthyridinyl),quinolanyl (2-quinolanyl), quinazolinyl (e.g., 2-quinazolinyl),cinnolinyl (e.g., 3-cinnolinyl), pteridinyl (e.g., 2-pteridinyl),carbazolyl (e.g., 2-carbazolyl, 3-carbazolyl), phenanthridinyl (e.g.,2-phenanthridinyl, 3-phenanthridinyl), acridinyl (e.g., 1-acridinyl,2-acridinyl), dibenzofuranyl (e.g., 1-dibenzofuranyl, 2-dibenzofuranyl),benzimidazolyl (e.g., 2-benzimidazolyl), benzisoxazolyl (e.g.,3-benzisoxazolyl), benzoxazolyl (e.g., 2-benzoxazolyl), benzoxadiazolyl(e.g., 4-benzoxadiazolyl), benzisothiazolyl (e.g., 3-benzisothiazolyl),benzothiazolyl (e.g., 2-benzothiazolyl), benzofuryl (e.g.,3-benzofuryl), benzothienyl (e.g., 2-benzothienyl) and the like.

[0066] Preferable are indolyl, imidazolyl and the like as “heteroaryl”for R².

[0067] Preferable are pyridyl, thienyl, furyl, imidazolyl and the likeas “heteroaryl” for R³.

[0068] The term “heteroarylalkyl” herein used includes the abovementioned “lower alkyl” substituted with at least one above-mentioned“heteroaryl” at any possible position. Examples of the heteroarylalkylare thiazolylmethyl (e.g., 4-thiazolylmethyl), thiazolylethyl (e.g.,5-thiazolyl-2-ethyl), benzothiazolylmethyl (e.g.,(benzothiazol-2-yl)methyl), indolylmethyl (e.g., (indol-3-yl)methyl),imidazolylmethyl (e.g., 4-imidazolylmethyl), benzothiazolylmethyl (e.g.,2-benzothiazolylmethyl), indazolylmethyl (e.g., 1-indazolylmethyl),benzotriazolylmethyl (e.g., 1-benzotriazolylmethyl), benzoquinolylmethyl(e.g., 2-benzoquinolylmethyl), benzimidazolylmethyl (e.g.,2-benzimidazolylmethyl), pyridylmethyl (e.g., 4-pyridylmethyl), and thelike.

[0069] Examples as “heteroarylalkyl” for R² are indolylmethyl (e.g.,indol-3-ylmethyl) and imidazolylmethyl (imidazol-5-ylmethyl) and thelike

[0070] In the present specification, the term “non-aromatic heterocyclicgroup” includes a 5 to 7 membered non-aromatic ring which contains oneor more hetero atoms selected from the group consisting of oxygen,sulfur, and nitrogen atoms in the ring and a condensed ring which areformed with two or more of the non-aromatic ring. Examples of thenon-aromatic heterocyclic group are pyrrolidinyl (e.g., 1-pyrrolidinyl,2-pyrrolidinyl), pyrrolinyl (e.g., 3-pyrrolinyl), imidazolidinyl (e.g.,2-imidazolidinyl), imidazolinyl (e.g., imidazolinyl), pyrazolidinyl(e.g., 1-pyrazolidinyl, 2-pyrazolidinyl), pyrazolinyl (e.g.,pyrazolinyl), piperidinyl (piperidino, 2-piperidinyl), piperazinyl(e.g., 1-piperazinyl), indolynyl (e.g., 1-indolynyl), isoindolinyl(e.g., isoindolinyl), morpholinyl (e.g., morpholino, 3-morpholinyl),4H-[1,2,4]oxaziazole-5-one, 1,2,3,4-tetrahydro- [1,8]naphtylidine,1,3-benzodioxolyl and the like.

[0071] The term “arylene” herein used means a divalent group of theabove-mentioned “aryl”. Examples of the arylene are phenylene,naphthylene, and the like. Mentioned in more detail, it is exemplifiedby 1,2-phenylene, 1,3-phenylen, 1,4-phenylene, and the like. Preferableis 1,4-phenylene.

[0072] The term “heteroarylene” herein used means a divalent group ofthe above-mentioned “heteroaryl”. Examples of the heteroarylene arethionphene-diyl, furan-diyl, pyridine-diyl, and the like. Mentioned inmore detail, it is exemplified by 2,5-thionphene-diyl, 2,5-furan-diyl,and the like.

[0073] In the present specification, the term “acyl” employed alone orin combination with other terms includes alkylcarbonyl in which alkylgroup is the above-mentioned “lower alkyl” and arylcarbonyl in whicharyl group is the above-mentioned “aryl”. Examples of the acyl areacetyl, propionyl, benzoyl, and the like. “Lower alkyl” and “aryl” maybe substituted respectively with substituents mentioned below.

[0074] The term “halogen” herein used means fluoro, chloro, bromo, andiodo. Fluoro, chloro, and bromo are preferred.

[0075] The term “lower alkyloxy” herein used are methyloxy, ethyloxy,n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy,tert-butyloxy, and the like. Methyloxy, ethyloxy, n-propyloxy,isopropyloxy and n-butyloxy are preferred.

[0076] The term “lower alkylthio” herein used are methylthio, ethylthio,and the like.

[0077] The term “lower alkenyloxy” herein used are vinyloxy, aryloxy,propenyloxy, crotonyloxy, isopentenyloxy and the like.

[0078] The term “lower alkyloxycarbonyl” herein used aremethyloxycarbonyl, ethyloxycarbonyl, n-propyloxycarbonyl,isopropyloxycarbonyl, and the like.

[0079] In the present specification, the term “halo(lower)alkyl”employed alone or in combination with other terms includes theabove-mentioned “lower alkyl” which is substituted with the abovementioned “halogen” at 1 to 8 positions, preferably, at 1 to 5. Examplesof the halo(lower)alkyl are trifluoromethyl, trichloromethyl,difluoroethyl, trifluoroethyl, dichloroethyl, trichloroethyl, and thelike. Preferable is trifluoromethyl.

[0080] Examples of the term “halo(lower)alkyloxy” herein used aretrifluoromethyloxy and the like.

[0081] Examples of the term “lower alkylsulfonyl” herein used aremethylsulfonyl, ethylsulfonyl and the like. Preferable ismethylsulfonyl.

[0082] Examples of the term “acyloxy” herein used are acetyloxy,propionyloxy, benzoyloxy and the like.

[0083] In the present specification, the term “optionally substitutedamino” includes amino or amino substituted with one or two of the abovementioned “lower alkyl”, “aralkyl”, “heteroarylalkyl” or “acyl”.Examples of the optionally substituted amino are amino, methylamino,dimethylamino, ethylmethylamino, diethylamino, benzylamino, acetylamino,benzoylamino and the like. Preferable are amino, methylamino,dimethylamino, ethylmethylamino, diethylamino and acetylamino.

[0084] Examples of the term “optionally substituted aminocarbonyl”herein used are aminocarbonyl, methylaminocarbonyl,dimethylaminocarbonyl, ethylmethylaminocarbonyl, diethylaminocarbonyland the like. Preferable is aminocarbonyl, diethylaminocarbonyl.

[0085] The substituents of “optionally substituted lower alkyl” arecycloalkyl, hydroxy, lower alkyloxy, mercapto, lower alkylthio, halogen,nitro, cyano, carboxy, lower alkyloxycarbonyl, halo(lower)alkyl,halo(lower)alkyloxy, optionally substituted amino, optionallysubstituted aminocarbonyl, acyl, acyloxy, optionally substitutednon-aromatic heterocyclic group, aryloxy (e.g., phenyloxy), aralkyloxy(e.g., benzyloxy), lower alkylsulfonyl, guanidino, azo group, optionallysubstituted ureide and the like. These substituents are able to locateat one or more of any possible positions.

[0086] Preferable are hydroxy, lower alkyloxy as substituents of“optionally substituted lower alkyl” for R².

[0087] Preferable are hydroxy, lower alkyloxy, optionally substitutednon-aromatic heterocyclic group as substituents of “optionallysubstituted lower alkyl” for R³.

[0088] The substituents of “optionally substituted naphtyl”, “optionallysubstituted isoquinolyl”, “optionally substituted quinolyl”, “optionallysubstituted 1,3-benzodioxolyl”, “optionally substituted benzofuranyl”,“optionally substituted benzothienyl”, “optionally substituted arylene”,“optionally substituted heteroarylene”, “optionally substituted aryl”,“optionally substituted heteroaryl”, “optionally substitutednon-aromatic heterocyclic group”, “optionally substituted aralkyl”,“optionally substituted heteroarylalkyl”, and “optionally substitutedureide” herein used are optionally substituted lower alkyl, cycloalkyl,lower alkenyl, lower alkynyl, hydroxy, lower alkyloxy, mercapto, loweralkylthio, halogen, nitro, cyano, carboxy, lower alkyloxycarbonyl,halo(lower)alkyl, halo(lower)alkyloxy, optionally substituted amino,optionally substituted aminocarbonyl, acyl, acyloxy, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted non-aromatic heterocyclic group, optionally substitutedaralkyl, lower alkylsulfonyl, guanidino group, azo group, or optionallysubstituted ureide and the like. These substituents are able to locateat one or more of any possible positions.

[0089] Preferable are halogen, nitro, cyano, lower alkyloxy, and thelike in the above-mentioned substituents as substituents for R⁴ of“optionally substituted arylene” and “optionally substitutedheteroarylene”. More preferable are unsubstituted “arylene” andunsubstituted “heteroarylene” as “optionally substituted arylene” and“optionally substituted heteroarylene”.

[0090] Preferable are optionally substituted lower alkyl, lower alkenyl,lower alkynyl, hydroxy, lower alkyloxy, mercapto, lower alkylthio,halogen, nitro, cyano, carboxy, lower alkyloxycarbonyl,halo(lower)alkyl, halo(lower)alkyloxy, optionally substituted amino,optionally substituted aminocarbonyl, acyl, acyloxy and the like in theabove-mentioned substituents, as substituents for R² of “optionallysubstituted aryl”. More preferable are aryl optionally substituted withhydroxy as “optionally substituted aryl”.

[0091] Preferable are optionally substituted lower alkyl, lower alkenyl,lower alkynyl, hydroxy, lower alkyloxy, mercapto, lower alkylthio,halogen, nitro, cyano, carboxy, lower alkyloxycarbonyl,halo(lower)alkyl, halo(lower)alkyloxy, optionally substituted amino,optionally substituted aminocarbonyl, acyl, acyloxy and the like in theabove-mentioned substituents, as substituents for R³ of “optionallysubstituted aryl”. More preferable are aryl optionally substituted withhydroxy, lower alkyloxy, halogen, or halo(lower)alkyl as “optionallysubstituted aryl”.

[0092] Preferable are optionally substituted lower alkyl, lower alkenyl,lower alkynyl, hydroxy, lower alkyloxy, mercapto, lower alkylthio,halogen, nitro, cyano, carboxy, lower alkyloxycarbonyl,halo(lower)alkyl, halo(lower)alkyloxy, optionally substituted amino,optionally substituted aminocarbonyl, acyl, acyloxy and the like in theabove-mentioned substituents, as substituents for R² of “optionallysubstituted heteroaryl”. More preferable are heteroaryl optionallysubstituted with hydroxy or halogen as “optionally substitutedheteroaryl”.

[0093] Preferable are optionally substituted lower alkyl, lower alkenyl,lower alkynyl, hydroxy, lower alkyloxy, mercapto, lower alkylthio,halogen, nitro, cyano, carboxy, lower alkyloxycarbonyl,halo(lower)alkyl, halo(lower)alkyloxy, optionally substituted amino,optionally substituted aminocarbonyl, acyl, acyloxy and the like in theabove-mentioned substituents, as substituents for R³ of “optionallysubstituted heteroaryl”. More preferable are heteroaryl optionallysubstituted with hydroxy, lower alkyloxy, halogen, or halo(lower)alkyl,as “optionally substituted heteroaryl”.

[0094] Preferable are optionally substituted lower alkyl, lower alkenyl,lower alkynyl, hydroxy, lower alkyloxy, mercapto, lower alkylthio,halogen, nitro, cyano, carboxy, lower alkyloxycarbonyl,halo(lower)alkyl, halo(lower)alkyloxy, optionally substituted amino,optionally substituted aminocarbonyl, acyl, acyloxy and the like in theabove-mentioned substituents, as substituents for R² of “optionallysubstituted aralkyl”. More preferable are aralkyl optionally substitutedwith hydroxy as “optionally substituted aralkyl”.

[0095] Preferable are optionally substituted lower alkyl, lower alkenyl,lower alkynyl, hydroxy, lower alkyloxy, mercapto, lower alkylthio,halogen, nitro, cyano, carboxy, lower alkyloxycarbonyl,halo(lower)alkyl, halo(lower)alkyloxy, optionally substituted amino,optionally substituted aminocarbonyl, acyl, acyloxy and the like in theabove-mentioned substituents, as substituents for R³ of “optionallysubstituted aralkyl”. More preferable are aralkyl optionally substitutedwith hydroxy, lower alkyloxy, halogen, or halo(lower)alkyl as“optionally substituted aralkyl”.

[0096] Preferable are optionally substituted lower alkyl, lower alkenyl,lower alkynyl, hydroxy, lower alkyloxy, mercapto, lower alkylthio,halogen, nitro, cyano, carboxy, lower alkyloxycarbonyl,halo(lower)alkyl, halo(lower)alkyloxy, optionally substituted amino,optionally substituted aminocarbonyl, acyl, acyloxy and the like in theabove-mentioned substituents, as substituents for R² of “optionallysubstituted heteroarylalkyl”. More preferable are heteroarylalkyloptionally substituted with halogen or hydroxy as “optionallysubstituted heteroarylalkyl”.

[0097] Preferable are optionally substituted lower alkyl, lower alkenyl,lower alkynyl, hydroxy, lower alkyloxy, mercapto, lower alkylthio,halogen, nitro, cyano, carboxy, lower alkyloxycarbonyl,halo(lower)alkyl, halo(lower)alkyloxy, optionally substituted amino,optionally substituted aminocarbonyl, acyl, acyloxy and the like in theabove-mentioned substituents, as substituents for R³ of “optionallysubstituted heteroarylalkyl”. More preferable are heteroarylalkyloptionally substituted with hydroxy, lower alkyloxy, halogen, orhalo(lower)alkyl as “optionally substituted heteroarylalkyl”.

[0098] Preferable are optionally substituted lower alkyl, cycloalkyl,lower alkenyl, lower alkynyl, hydroxy, lower alkyloxy, lower alkenyloxy,mercapto, lower alkylthio, halogen, nitro, cyano, carboxy, loweralkyloxycarbonyl, halo(lower)alkyl, halo(lower)alkyloxy, optionallysubstituted amino, optionally substituted aminocarbonyl, acyl, acyloxyand the like, as substituents of “optionally substituted naphtyl”,“optionally substituted isoquinolyl”, “optionally substituted quinolyl”,“optionally substituted 1,3-benzodioxolyl”, “optionally substitutedbenzofuranyl”, “optionally substituted benzothienyl”. More preferableare halogen, lower alkyl, cycloalkyl, lower alkenyl, lower alkynyl,lower alkyloxy, lower alkenyloxy, lower alkylthio, halo(lower)alkyl,hydroxy, carboxy, lower alkyloxycarbonyl, aminocarbonyl, acyl, nitro,cyano, or optionally substituted amino as substituent. Much morepreferable are lower alkyl, lower alkyloxy, halogen, lower alkylthio oroptionally substituted amino.

BEST MODE FOR CARRYING OUT THE INVENTION

[0099] Compounds (I) of the present invention are able to be synthesizedin accordance with the procedure described in WO97/27174 (Method A to F)and WO99/04780.

[0100] The term “compound of the present invention” herein used includesa pharmaceutically acceptable salt or its solvate. The salt isexemplified by a salt with alkali metals (e.g., lithium, sodium,potassium, and the like), alkaline earth metals (e.g., magnesium,calcium, and the like), ammonium, organic bases, amino acids, mineralacids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid,sulfuric acid, and the like), or organic acids (e.g., acetic acid,citric acid, maleic acid, fumaric acid, benzenesulfonic acid,p-toluenesulfonic acid, and the like) or by a solvate with anappropriate solvent. These salts and solvates can be formed by the usualmethod. Preferable are hydrates as a solvates. These hydrates cancoordinate with any water molecules.

[0101] The present invention includes prodrugs of compounds of thepresent invention. Prodrug is a derivative of the compound having agroup which can be decomposed chemically or metabolically, and suchprodrug is a compound according to the present invention which becomespharmaceutically active by means of solvolysis or by placing thecompound in vivo under a physiological condition. The method of bothselection and manufacture of appropriate prodrug derivatives isdescribed in, for example. Design of Prodrugs, Elsevier, Amsterdam,1985. For instance, prodrugs such as an ester derivative, optionallysubstituted alkyloxycarbonyl, which is prepared by reacting a basal acidcompound with a suitable alcohol, or an amide derivative, optionallysubstituted alkylaminocarbonyl, which is prepared by reacting a basalacid compound with a suitable amine are exemplified when the compoundsaccording to present invention have a carboxylic group. Particularlypreferred esters as prodrugs are methyl ester, ethyl ester, n-propylester, isopropyl ester, n-butyl ester, isobutyl ester, tert-butyl ester,morpholinoethyl ester, and N,N-diethylglycolamido ester, and the like.For instance, prodrugs such as an acyloxy derivative which is preparedby reacting a basal hydroxy compound with a suitable acyl halide or asuitable acid anhydride are exemplified when the compounds according topresent invention have a hydroxy group.. Particularly preferred acyloxyderivatives as prodrugs —OCOC₂H₅, —OCO(t-Bu), —OCOC₁₅H₃,—OCO(m-COONa—Ph), —OCOCH₂CH₂COONa, —OCOCH(NH₂)CH₃, —OCOCH₂N(CH₃)₂, andthe like. For instance, prodrugs such as an amide derivative which isprepared by reacting a basal amino compound with a suitable acid halideor a suitable acid anhydride are exemplified when the compoundsaccording to present invention have an amino group. Particularlypreferred amide as prodrugs are —NHCO(CH₂)₂₀CH₃, —NHCOCH(NH₂)CH₃, andthe like.

[0102] The compound of the present invention is not restricted to anyparticular isomers but includes all possible isomers and racemicmodifications.

[0103] The compound of the present invention has an excellent activityagainst inhibiting MMP-12, as described in the following test example.

[0104] Definitely, the compounds of the present invention are useful inthe treatment of diseases such as chronic obstructive pulmonary disease,osteoarthritis, rheumatoid arthritis, corneal ulceration, periodontaldisease, advanced virus infection (e.g., HIV infection),arteriosclerosis obliterans, arteriosclerotic aneurysm, atherosclerosis,restenosis, sepsis, septic shock, coronary thrombosis, aberrantangiogenesis, scleritis, multiple sclerosis, open angle glaucoma,retinopathies, proliferative retinopathy, neovascular glaucoma,pterygium, keratitis, epidermolysis bullosa, psoriasis, diabetes,nephritis, neurodegengerative disease, inflammation, osteoporosis,deossification, gingivitis, tumor growth, tumor angiogenesis, oculartumor, angiofibroma, hemangioma, fever, hemorrhage, coagulation,cachexia, anorexia, acute infection, shock, autoimmune disease, malaria,Crohn disease, meningitis, heart failure, asthmatic respiratory tractdisease, arteriosclerosis, and gastric ulcer. The compounds are expectedespecially as compositions of treating for chronic obstructive pulmonarydisease.

[0105] When the compound of the present invention is administered to aperson for the treatment of the above diseases, it can be administeredorally as powder, granules, tablets, capsules, pilulae, and liquidmedicines, or parenterally as injections, suppositories, percutaneousformulations, insufflation, or the like. An effective dose of thecompound is formulated by being mixed with appropriate medicinaladmixtures such as excipient, binder, penetrant, disintegrators,lubricant, and the like if necessary. Parenteral injections are preparedby sterilizing the compound together with an appropriate carrier.

[0106] The dosage varies with the conditions of the patients,administration route, their age, and body weight. In the case of oraladministration, the dosage can generally be between 0.1 to 100mg/kg/day, and preferably 0.1 to 20 mg/kg/day for adult.

[0107] The following examples are provided to further illustrate thepresent invention and are not to be constructed as limiting the scopethereof.

[0108] Abbreviations described below are used in the following examples.

[0109] Me: methyl

[0110] Et: ethyl

[0111] n-Pr: n-propyl

[0112] i-Pr: isopropyl

[0113] n-Bu: n-butyl

[0114] i-Bu: isobutyl

[0115] t-Bu: tert-butyl

[0116] Ph: phenyl

[0117] Bn: benzyl

[0118] Indol-3-yl methyl: indol-3-ylmethyl

[0119] DMSO: dimethyl sulfoxide

EXAMPLE Example 1 The Preparation of the Compound (A-1)

[0120]

[0121] (Process 1)

[0122] To a suspension of L-valine methyl ester hydrochloride (1) (3.30g, 19.7 mmol), and N-methylmorpholine (5.7 ml, 51.8 mmol) intetrahydrofuran (100 ml) was added in an ice bath 4-iodobenzenesulfonylchloride (2) (5.00 g, 16.5 mmol). After the mixture was stirred at 0° C.for 0.5 h and then at room temperature for 2.5 h, the reaction mixturewas poured into ice-2mol/L hydrochloric acid and was extracted withethyl acetate. The organic layer was successively washed with saturatedsodium hydrogencarbonate aqueous solution and brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was crystallized from ethyl acetate-hexane to obtain the product(3) (4.32 g, yield: 65.8%) with a melting point of 99-102° C.

[0123] IR(KBr, v max cm⁻¹) 3271, 1740, 1568, 1346, 1161

[0124]¹H NMR (CDCl₃,δppm): 0.87 (d, J=6.6 Hz, 3H), 0.96 (d, J=6.8 Hz,3H), 2.07 (m, 1H), 3.49 (s, 3H), 3.74 (m, 1H), 5.10 (d, J=10.4 Hz, 1H),7.54 (d, J=8.8 Hz, 2H), 7.86 (d, J=8.4 Hz, 2H)

[0125] [α]_(D)+6.7±0.9 (c=0.509, DMSO, 24° C.)

[0126] Elemental analysis (C₁₂H₁₆NO₄SI.0.1H₂O)

[0127] Calcd.: C;36.12, H;4.09, N;3.51, S;8.04, I;31.80

[0128] Found: C;36.32, H;4.08, N;3.58, S;7.97, I;31.57

[0129] (Process 2)

[0130] To a solution of compound (3) (1.00 g, 2.52 mmol) indimethyl-formamide (6 ml) was added 2-ethynylnaphthalene (580 mg, 3.78mmol) and the mixture was degassed under argon atmosphere.Bis(triphenylphosphine)-palladium (II) dichloride (44.0 mg, 62.7 μmol),copper iodide (I) (24.0 mg, 0.126 μmol) and triethylamine (1.05 ml, 7.56mmol) were added to it and then the mixture was degassed under argonatmosphere again. After the reaction mixture was stirred at 50° C. for15 h, it was poured into ice-2mol/L hydrochloric acid and was extractedwith ethyl acetate. The organic layer was washed successively with 5%saturated sodium hydrogencarbonate aqueous solution and brine, driedover anhydrous sodium sulfate and evaporated under reduced pressure. Theresidue was subjected to silica gel column chromatography and thefraction eluted with hexane/ethyl acetate/chloroform=3/1/1 to 2/1/1 wascollected, recrystallized from acetone/n-hexane to yield the product (4)(848 mg, yield: 80.0%) with a melting point of 152-154° C.

[0131] IR (KBr, v max cm⁻¹) 3288, 2216, 1736, 1597, 1348, 1169

[0132]¹H NMR (CDCl₃, δppm): 0.89 (d, J=6.9 Hz, 3H), 0.98 (d, J=6.6 Hz,3H), 2.06 (m, 1H), 3.50 (s, 3N), 3.73 (m, 1H), 5.12 (d, J=10.2 Hz, 1H),7.51-7.60 (m, 3H), 7.67 (d, J=8.7 Hz, 2H), 7.81-7.85 (m, 5H), 8.08 (s,1H)

[0133] [α]_(D)−5.7±10.9 (c=0.504, DMSO, 24° C.)

[0134] Elemental analysis (C₂₄H₂₃NO₄S)

[0135] Calcd.: C;68.39, H;5.50, N;3.32, S;7.61

[0136] Found: C;68.32, H;5.47, N;3.41, S;7.38

[0137] (Process 3)

[0138] To a solution of compound (4) (818 mg, 1.94 mmol) indimethylsulfoxide (16.4 ml) was added at room temperature 1 mol/Laqueous sodium hydroxide solution (5.80 ml, 5.82 mmol). The solution wasstirred at 60° C. for 15 h and poured into ice-2 mol/L hydrochloricacid. The mixture was extracted with ethyl acetate and the organic layerwas washed with brine, dried over anhydrous sodium sulfate andevaporated under reduced pressure. The residue was crystallized fromacetone-water to give the product (A-1) (763 mg, yield: 96.5%) with amelting point of 171-173° C.

[0139] IR (KBr, v max cm⁻¹) 3336, 2214, 1709, 1346, 1167

[0140]¹H NMR (DMSO-d₆, δppm): 0.82 (d, J=6.6 Hz, 3H), 0.84 (d, J=6.6 Hz,3H), 1.97 (m, 1H), 3.73 (br s, 1H), 7.58-7.67 (m, 3H), 7.76 (d, J=8.4Hz, 2H), 7.83 (d, J=8.7 Hz, 2H), 7.90-8.01 (m, 3H), 8.15 (d, J=9.0 Hz,1H), 8.25 (s, 1H), 12.70 (br s, 1H)

[0141] [α]_(D)+11.4 ±1.0 (c=0.511, DMSO, 24° C.)

[0142] Elemental analysis (C₂₃H₂₁NO₄S.0.3H₂O)

[0143] Calcd.: C;66.9, H;5.27, N;3.39, S;7.77

[0144] Found: C;66.84, H;5.28, N;3.41, S;7.66

[0145] The following compound (A-2) to compound (A-30), compound (B-1)to compound (B-29), compound (C-1) to compound (C-2), compound (D-1) tocompound (D-2), compound (E-1) to compound (E-10), compound (F-1) tocompound (F-2), and compound (G-1) were synthesized in a manner similarto Example 1.

[0146] Their results were shown in tables 1 to 5, tables 6 to 9, table10, table 11, table 12 to 13, table 14, and table 15. TABLE 1

Example Compound No. No. R² R⁶ * ¹H-NMR (DMSO-d₆) 2 A-2 Bn

R 2.74(dd, J=9.2, 13.6Hz, 1H), 2.98(dd, J=5.2, 13.6Hz, 1H), 3.91(m, 1H),7.13-7.28(m, 5H), 7.55-7.65(m, 7H), 7.93-8.04(m, 3H), 8.26(s, 1H),8.44(d, J=9.0Hz, 1H), 12.80(brs, 1H) 3 A-3 Bn

S 2.75(dd, J=9.3, 13.5Hz, 1H), 2.98(dd, J=5.4, 14.1Hz, 1H), 3.93(m, 1H),7.10-7.23(m, 5H), 7.55-7.67(m, 7H), 7.96-8.01(m, 3H), 8.25(s, 1H),8.42(d, J=9.0Hz, 1H), 12.00(brs, 1H) 4 A-4 (4-OH- indole- 3- yl)methyl

R 2.79(dd, J=8.4, 14.4Hz, 1H), 2.99(dd, J=6.0, 14.4Hz, 1H), 3.95(m, 1H),6.59(dd, J=2.4, 8.7Hz, 1H), 6.72(d, J=2.4Hz, 1H), 6.98(d, J=2.4Hz, 1H),7.11(d, J=8.7Hz, 1H), 7.50-7.70(m, 7H), 7.90-8.10(m, 3H), 8.24(s, 1H),8.34(d, J=8.1Hz, 1H), 8.59(s, 1H), 10.50(s, 1H), 12.65(br s, 1H) 5 A-5i-Pr

R 0.81(d, J=6.9Hz, 3H), 0.84(d, J=6.9Hz, 3H), 1.97(m, 1H), 3.55(s, 1H),7.57-7.63(m, 2H), 7.58-7.67(m, 3H), 7.76(d, J=8.4Hz, 2H), 7.83(d,J=9.0Hz, 2H), 7.95-8.01(m, 3H), 8.13(s, 1H), 8.25(s, 1H), 12.4-12.8(brs,1H) 6 A-6 i-Pr

S 0.81(d, J=6.9Hz, 3H), 0.84(d, J=6.9Hz, 3H), 1.97(m, 1H), 3.48(br, s,1H), 7.58-7.67(m, 3H), 7.76(d, J=8.4Hz, 2H), 7.83(d, J=8.7Hz, 2H),7.90-8.01(m, 3H), 8.15(d, J=9.0Hz, 1H), 8.25(s, 6H), 12.60-12.80(hrs,1H) 7 A-7 Me

R 1.19(d, J=7.4Hz, 3H), 3.83(m, 1H), 7.54-7.70(3H), 7.78(d, J=8.2Hz,2H), 7.85(d, J=8.8Hz, 2H) 7.92-8.06(m, 3H), 8.25(s, 1H), 8.16(brs, 1H),12.65(brs, 1H) 8 A-8 Me

S 1.19(d, J=7.4Hz, 3H), 3.83(m, 1H), 7.54-7.70(3H), 7.78(d, J=8.2Hz,2H), 7.85(d, J=8.8Hz, 2H) 7.92-8.06(m, 3H), 8.25(s, 1H), 8.31(brs, 1H),12.70(brs, 1H)

[0147] TABLE 2 Example Compound No. No. R² R⁶ * ¹H-NMR (DMSO-d₆) 9 A-9 H

3.65(d, J=4.8Hz, 2H), 7.66-7.69(3H), 7.78(d, J=8.4Hz, 2H), 7.86(d,J=8.8Hz, 2H), 7.92-8.04(m, 3H), 8.19(m, 1H), 8.25(s, 1H), 12.70(brs, 1H)10 A-10 i-Bu

R 0.74(d, J=6.2Hz, 3H), 0.83(d, J=6.2Hz, 3H), 1.41(t, J=6.6Hz, 2H),1.60(m, 1H), 3.65(m, 1H), 7.56-7.70(m, 3H), 7.77(d, J=8.4Hz, 2H),7.83(d, J=8.4Hz, 2H), 7.92-8.04(m, 4H), 8.10(br, 1H), 8.26(s, 1H) 11A-11 i-Bu

S 0.73(d, J=6.6Hz, 3H), 0.83(d, J=6.6Hz, 3H), 1.38-1.45(m, 2H), 1.60(m,1H), 3.70(m, 1H), 7.56-7.70(m, 3H), 7.77(d, J=8.4Hz, 2H), 7.83(d,J=8.4Hz, 2H), .7.94-8.04(m, 3H), 8.26(s, 1H), 8.30(br s, 1H), 12.70(br,1H) 12 A-12 4-OH- Ph

R 4.78(s, 1H), 6.64(d, J=8.8Hz, 2H), 7.07(d, J=8.8Hz, 1H), 7.55-7.64(m,3H), 7.68(d, J=8.8Hz, 2H), 7.77(d, J=8.8Hz, 2H), 7.93-8.04(m, 3H),8.25(s, 1H), 8.65(br, 1H), 9.45(brs, 1H) 13 A-13 4-OH- Bn

R 2.68(dd, J=7.4, 14.0Hz, 1H), 2.85(dd, J=5.8, 14.0Hz, 1H), 3.72(m, 1H),6.61(d, J=8.4Hz, 2H), 6.95(d, J=8.4Hz, 2H), 7.55-7.70(m, 7H),7.92-8.04(m, 3H), 8.25(s, 1H), 9.20(br, 1H) 14 A-14 Indole- 3- ylmethyl

R 2.89(dd, J=8.0, 14.5Hz, 1H), 3.09(dd, J=5.4, 14.5Hz, 1H), 3.94(m, 1H),6.90-7.10(m, 3H), 7.27-7.40(m, 2H), 7.52-7.70(m, 7H), 7.92-8.03(m, 3H),8.25(s, 1H), 8.32(m, 1H), 10.81(s, 1H) 15 A-15 Indole- 3- ylmethyl

S 2.89(dd, J=8.6, 14.2Hz, 1H), 3.09(dd, J=6.2, 14.2Hz, 1H), 3.95(m, 1H),6.91-7.14(m, 3H), 7.30-7.38(m, 2H), 7.52-7.67(m, 7H), 7.94-8.06(m, 3H),8.25(s, 1H), 8.37(m, 1H), 10.82(s, 1H), 12.71(br, 1H) 16 A-16MeS—CH₂—CH₂—

R 1.60-2.00(m, 2H), 1.96(s, 3H), 2.30-2.50(m, 2H), 3.91(s, 1H),7.50-7.70(m, 3H), 7.78(d, J=8.4Hz, 2H), 7.83(d, J=8.4Hz, 2H),7.90-8.10(m, 3H), 8.25(s, 1H), 8.33(d, J=8.1Hz, 1H), 12.75(br s, 1H).

[0148] TABLE 3 Example Compound No. No. R² R⁶ * ¹H-NMR (DMSO-d₆) 17 A-17MeS—CH₂—CH₂—

R 1.71-1.88(m, 2H), 1.96(s, 3H), 2.25-2.46(m, 2H) 3.91(s, 1H),7.57-7.68(m, 3H), 7.77(d, J=8.8Hz, 2H), 7.83(d, J=8.8Hz, 2H),7.96-8.02(m, 3H), 8.26(s, 1H), 8.34(d, J=8.8Hz, 1H), 12.80(brs, 1H) 18A-18 HOOC—CH₂—

R 2.46(dd, J=7.2, 16.5Hz, 1H), 2.63(dd, J=6.6, 16.5Hz, 1H), 4.11(m, 1H),7.56-7.64(m, 2H), 7.66(dd, J=1.8, 8.4Hz, 1H), 7.77(d, J=8.4Hz, 2H),7.84(d, J=8.4Hz, 2H), 7.94-8.03(m, 3H), 8.26(s, 1H), 8.38(br s, 1H),12.67(br s, 2H) 19 A-19 HOOC—CH₂—

S 2.46(dd, J=7.2, 16.5Hz, 1H), 2.63 (dd, J=6.6, 16.5Hz, 1H), 4.11(m,1H), 7.57-7.64(m, 2H), 7.66(dd, J=1.5, 8.4Hz, 1H), 7.77(d, J=8.7Hz, 2H),7.84(d, J=8.7Hz, 2H), 7.94-8.03(m, 3H), 8.26(s, 1H), 8.38(br s, 1H),12.69(br s, 2H) 20 A-20 HO—CH₂—

R 3.52(dd, J=6.0, 11.1Hz, 1H), 3.56 (dd, J=5.4, 11.1Hz, 1H), 3.82(dt,J=8.7, 5.4Hz, 1H), 5.10(br s, 1H), 7.56-7.64(m, 2H), 7.65(dd, J=1.5,8.4Hz, 1H), 7.77(d, J=8.4Hz, 2H), 7.86(d, J=8.4Hz, 2H), 7.94-8.03(m,3H), 8.20(d, J=9.0Hz, 1H), 8.26(s, 1H), 12.57(br s, 1H) 21 A-21 Bn

R 2.37(dd, J=9.2, 13.8Hz, 1H), 2.96 (dd, J=5.9, 13.4Hz, 1H), 3.90(m,1H), 5.10(s, 2H), 7.00(d, J=8.8Hz, 1H), 7.05-7.25(7H), 7.56(s, 4H),8.39(d, J=9.2Hz, 1H), 12.75(br s, 1H) 22 A-22 Bn

S 2.37(dd, J=9.2, 13.8Hz, 1H), 2.96 (dd, J=5.9, 13.4Hz, 1H), 3.90(m,1H), 5.10(s, 2H), 7.00(d, J=8.8Hz, 1H), 7.05-7.25(7H), 7.56(s, 4H),8.39(d, J=9.2Hz, 1H), 12.75(br s, 1H) 23 A-23 Me

R 1.17(d, J=7.2Hz, 3H), 3.80(q, J=8.4Hz, 1H), 6.10(s, 2H), 7.00(dd,J=1.2, 5.7Hz, 1H), 7.13-7.15(m, 2H), 7.68(d, J=6.9Hz, 2H), 7.79(d,J=6.9Hz, 2H), 8.26(d, J=8.4Hz, 1H), 12.66(br, 1H)

[0149] TABLE 4 Example Compound No. No. R² R⁶ * ¹H-NMR (DMSO-d₆) 24 A-24Me

S 1.17(d, J=7.2Hz, 3H), 3.80(m, 1H), 6.10(s, 2H), 7.00(d, J=5.7Hz, 1H),7.13-7.15(m, 2H), 7.68(d, J=6.9Hz, 2H), 7.79(d, J=6.9Hz, 2H), 8.30(m,1H), 12.60(br, 1H) 25 A-25 i-Pr

R 0.80(d, J=6.3Hz, 3H), 0.83(d, J=6.3Hz, 3H), 1.93(m, 1H), 3.53(m, 1H),6.10(s, 2H), 7.00(d, J=8.4Hz, 1H), 7.13(d, J=8.4Hz, 1H), 7.15(s, 1H),7.66(d, J=8.7Hz, 2H), 7.78(d, J=8.7Hz, 2H), 8.11(m, 1H), 12.60(brs, 1H)26 A-26 i-Pr

S 0.80(d, J=6.6Hz, 3H), 0.83(d, J=6.6Hz, 3H), 1.93(m, 1H), 3.53(m, 1H),6.10(s, 2H), 6.99(d, J=7.5Hz, 1H), 7.14(d, J=7.5Hz, 1H), 7.15(s, 1H),7.66(d, J=8.1Hz, 2H), 7.78(d, J=8.1Hz, 2H), 8.11(m, 1H), 12.62(br, 1H)27 A-27 H

3.62(d, J=4.5Hz, 2H), 6.10(s, 2H), 7.00(m, 1H), 7.12-7.15(m, 2H),7.67-7.70(m, 2H), 7.80(d, J=8.7Hz, 2H), 8.16(m, 1H), 12.71(brs, 1H) 28A-28 MeS—CH₂—CH₂—

R 1.63-1.90(m, 2H), 1.95(s, 1H), 2.26-2.45(m, 2H), 3.87(m, 1H), 6.10(s,2H), 7.00(d, J=7.8Hz, 2H), 7.12-7.15(m, 2H), 7.68(d, J=8.4Hz, 2H),7.78(d, J=8.4Hz, 2H), 8.32(d, J=8.7Hz, 1H), 12.78(br, 1H) 29 A-29 i-Pr

R 0.79(d, J=6.9Hz, 3H), 0.83(d, J=6.9Hz, 3H), 1.94(m, 1H), 3.52(m, 1H),4.24-4.33(m, 4H), 6.92(d, J=8.1Hz, 1H), 7.04-7.12(m, 2H), 7.66(d,J=8.7Hz, 2H), 7.77(d, J=8.7Hz, 2H), 8.14(d, J=9.3Hz, 1H), 12.66(br s,1H) 30 A-30 i-Pr

S 0.79(d, J=6.6Hz, 3H), 0.83(d, J=6.9Hz, 3H), 1.95(m, 1H), 3.53(m, 1H),4.20-4.40(m, 4H), 6.93(d, J=7.8Hz, 1H), 7.05-7.14(m, 2H), 7.67(d,J=8.1Hz, 2H), 7.78(d, J=8.1Hz, 2H), 8.17(d, J=8.7Hz, 1H), 12.67(br s,1H) 31 A-31 Bn

R 2.73(dd, J=9.3, 13.5Hz, 1H), 2.96(dd, J=5.4, 13.5Hz, 1H), 3.90(m, 1H),6.92(dd, J=0.6, 8.1Hz, 1H), 7.04-7.27(m, 7H), 7.50-7.60(m, 4H), 8.40(d,J=9.3Hz, 1H), 12.77(br s, 1H)

[0150] TABLE 5 Example Compound No. No. R² R⁶ * ¹H-NMR (DMSO-d₆) 32 A-32Bn

R 2.74(dd, J=9.3, 13.5Hz, 1H), 2.97(dd, J=5.4, 13.5Hz, 1H), 3.90(s, 3H),3.92(m, 1H), 7.13-7.27(m, 6H), 7.39(d, J=2.7Hz, 1H), 7.57-7.64(m, 5H),7.89(dd, J=4.5, 9.0Hz, 2H), 8.17(s, 1H), 8.45(d, J=8.7Hz, 1H), 12.83(brs, 1H) 33 A-33 Bn

S 2.74(dd, J=9.3, 13.5Hz, 1H), 2.98(dd, J=5.4, 13.5Hz, 1H), 3.91(s, 3H),3.92(m, 1H), 7.12-7.27(m, 6H), 7.39(d, J=2.4Hz, 1H), 7.57-7.65(m, 5H),7.89(dd, J=4.5, 8.7Hz, 2H), 8.17(s, 1H), 8.44(d, J=9.0Hz, 1H), 12.81(brs, 1H) 34 A-34 i-Pr

R 0.81(d, J=6.6Hz, 3H), 0.84(d, J=6.9Hz, 3H), 1.96(m, 1H), 3.55(m, 1H),3.90(s, 3H), 7.24(dd, J=2.7, 9.0Hz, 1H), 7.39(d, J=2.1Hz, 1H), 7.60(dd,J=1.5, 8.7Hz, 1H), 7.73(d, J=8.4Hz, 2H), 7.81(d, J=8.4Hz, 2H), 7.88(dd,J=3.3, 9.0Hz, 2H), 8.16(s, 1H), 8.19(br s, 1H), 12.75(br s, 1H) 35 A-35Me

R 1.18(d, J=7.2Hz, 3H), 3.82(m, 1H), 3.90(s, 3H), 7.24(dd, J=2.4, 9.0Hz,1H), 7.39(d, J=2.4Hz, 1H), 7.60(dd, J=1.8, 8.7Hz, 1H), 7.75(d, J=8.4Hz,2H), 7.82(d, J=8.7Hz, 2H), 7.89(dd, J=3.9, 9.3Hz, 2H), 8.16(s, 1H),8.29(d, J=7.8Hz, 1H), 12.75(br s, 1H)

[0151] TABLE 6

Example Compound No. No. R² R⁶ * ¹H-NMR (DMSO-d₆) 31 B-1 Bn

R 2.77(dd, J=9.6, 13.8Hz, 1H), 3.02(d, J=5.1, 13.8Hz, 1H), 3.98(m, 1H),7.16-7.27(m, 5H), 7.28(d, J=3.9Hz, 1H), 7.33(d, J=3.9Hz, 1H),7.57-7.66(m, 3H), 7.95-8.03(m, 3H), 8.26(d, J=0.9Hz, 1H), 8.75(d,J=8.1Hz, 1H), 12.91(br s, 1H) 32 B-2 Bn

S 2.76(dd, J=9.4, 13.8Hz, 1H), 3.02(dd, J=4.6, 13.8Hz, 1H), 3.98(m, 1H),7.15-7.30(m, 5H), 7.28(d, J=3.8Hz, 1H), 7.33(d, J=3.8Hz, 1H),7.56-7.67(m, 3H), 7.94-8.05(m, 3H), 8.26(s, 1H), 8.79(br s, 1H),12.96(br, 1H) 33 B-3 (Indole- 3- yl)methyl

R 2.95(dd, J=8.1, 14.1Hz, 1H), 3.14(dd, J=5.7, 14.1Hz, 1H), 4.00(dd,J=6.3, 7.2Hz, 1H), 6.97(t, J=7.5Hz, 1H), 7.06(t, J=7.2Hz, 1H), 7.12(d,J=2.4Hz, 1H), 7.23(d, J=3.9Hz, 1H), 7.28(d, J=3.9Hz, 1H), 7.33(d,J=8.1Hz, 2H), 7.43(d, J=7.5Hz, 1H), 7.57-7.67(m, 3H), 7.95-8.03(m, 3H),8.25(s, 1H), 8.58(br s, 1H), 10.83(s, 1H) 34 B-4 i-Pr

R 0.83(d, J=6.9Hz, 3H), 0.88(d, J=6.6Hz, 3H), 2.01(m, 1H), 3.64(m, 1H),7.46(d, J=3.9Hz, 1H), 7.54(d, J=3.9Hz, 1H), 7.57-7.66(m, 3H),7.94-8.02(m, 3H), 8.26(d, J=1.2Hz, 1H), 8.50(d, J=9.0Hz, 1H), 12.77(brs, 1H) 35 B-5 i-Pr

S 0.83(d, J=6.6Hz, 3H), 0.88(d, J=7.0Hz, 3H), 2.02(m, 1H), 3.64(s, 1H),7.46(d, J=4.0Hz, 1H), 7.54(d, J=4.0Hz, 1H), 7.58-7.66(m, 3H),7.96-8.02(m, 3H), 8.27(s, 1H), 8.52(brs, 1H), 12.80(brs, 1H) 36 B-6 Me

R 1.25(d, J=7.2Hz, 3H), 3.91(m, 1H), 7.48(d, J=3.9Hz, 1H), 7.55-7.67(m,4H), 7.95-8.02(m, 3H), 8.26(s, 1H), 8.63(d, J=6.9Hz, 1H), 12.81(br s,1H) 37 B-7 Me

S 1.24(d, J=7.2Hz, 3H), 3.89(s, 1H), 7.48(d, J=4.0Hz, 1H), 7.56-7.66(m,4H), 7.96-8.02(m, 3H), 8.27(s, 1H), 8.62(brs, 1H), 12.79(brs, 1H)

[0152] TABLE 7 Example Compound No. No. R² R⁶ * ¹H-NMR (DMSO-d₆) 38 B-84-OH- Ph

R 4.87(s, 1H), 6.68(d, J=8.4Hz, 2H), 7.13(d, J=8.7Hz, 2H), 7.39(d,J=3.9Hz, 1H), 7.46(d, J=3.9Hz, 1H), 7.59-7.65(m, 3H), 7.96-8.01(m, 3H),8.25(s, 1H), 9.01(s, 1H), 9.49(s, 1H), 12.94(br s, 1H) 39 B-9 H

3.73(s, 2H), 7.49(d, J=3.9Hz, 1H), 7.57-7.66(m, 4H), 7.95-8.02(m, 3H),8.26(s, 1H), 8.53(br s, 1H), 12.82(br s, 1H) 40 B-10 MeS—CH₂—CH₂—

R 1.7-2.1(m, 2H), 2.00(s, 3H), 2.3-2.6(m, 2H), 3.97(s, 1H), 7.4-7.7(m,5H), 7.9-8.1(m, 3H), 8.26(s, 1H), 8.65(br s, 1H), 12.78(br s, 1H). 41B-11 MeS—CH₂—CH₂—

S 1.76-1.93(m, 2H), 2.00(s, 3H), 2.35-2.50(m, 2H), 3.97(s, 1H), 7.47(d,J=3.8Hz, 1H), 7.54-7.66(m, 4H), 7.96-8.02(m, 3H), 8.26(s, 1H), 8.65(brs, 1H), 12.80(br s, 1H) 42 B-12 HOOC—CH₂—

R 2.4-2.8(m, 2H), 4.19(s, 1H), 7.40-7.70(m, 5H), 7.85-8.06(m, 3H),8.27(s, 1H), 8.68(br s, 1H), 12.74(br s, 2H). 43 B-13 i-Bu

R 0.79(d, J=6.3Hz, 3H), 0.86(d, J=6.6Hz, 3H), 1.37-1.54(m, 2H), 1.64(m,1H), 3.78(m, 1H), 7.47(d, J=3.9Hz, 1H), 7.54(d, J=3.9Hz, 1H), 7.57-7.67(m, 3H), 7.94-8.03(m, 3H), 8.26(s, 1H), 8.63(d, J=9.0Hz, 1H), 12.79(brs, 1H) 44 B-14 4-OH- Bn

R 2.76(dd, J=9.3, 13.5Hz, 1H), 3.01 (dd, J=4.8, 13.5Hz, 1H), 3.90(m,1H), 6.65(d, J=8.4Hz, 2H), 6.97(d, J=8.4Hz, 2H), 7.31(d, J=3.9Hz, 1H),7.35(d, J=3.9Hz, 1H), 7.56-7.67(m, 3H), 7.94-8.03(m, 3H), 8.26(s, 1H),8.72(d, J=8.1Hz, 1H), 9.26(s, 1H), 12.86(br s, 1H) 45 B-15 HOOC—CH₂—CH₂—

R 1.71(m, 1H), 1.93(m, 1H), 2.27(t, J=7.5Hz, 2H), 3.89(dd, J=4.8, 8.7Hz,1H), 7.47(d, J=3.9Hz, 1H), 7.54(d, J=3.9Hz, 1H), 7.58-7.67(m,3H),7.94-8.03(m, 3H), 8.27(s, 1H), 8.66(br s, 1H), 12.57(br s, 2H)

[0153] TABLE 8 Example Compound No. No. R² R⁶ * ¹H-NMR (DMSO-d₆) 46 B-16Bn

R 2.76(dd, J=9.3, 13.5Hz, 1H), 3.01(dd, J=4.8, 13.5Hz, 1H), 3.90(s, 3H),3.98(m, 1H), 7.16-7.27(m, 6H), 7.27(d, J=3.9Hz, 1H), 7.30(d, J=3.9Hz,1H), 7.40(d, J=2.4Hz, 1H), 7.59(dd, J=1.8, 8.7Hz, 1H), 7.89(dd, J=5.1,8.7Hz, 2H), 8.17(s, 1H), 8.77(d, J=8.4Hz, 1H), 12.96(br s, 1H) 47 B-17Bn

R 2.77(dd, J=9.9, 13.8Hz, 1H), 3.03 (dd, J=4.5, 13.5Hz, 1H), 3.89(brs,1H), 7.15-7.30(m, 5H), 7.32(d, J=3.9Hz, 1H), 7.43(d, J=3.9Hz, 1H),7.57-7.76(m, 3H), 7.88(d, J=7.2Hz, 1H), 8.05(d, J=7.8Hz, 1H), 8.08(d,J=8.1Hz, 1H), 8.29(d, J=7.8Hz, 1H), 8.78(d, J=7.8Hz, 1H), 12.95(brs, 1H)48 B-18 Bn

R 2.76(dd, J=9.6, 14.0Hz, 1H), 3.03(dd, J=4.6, 14.0Hz, 1H), 4.01(m, 1H),7.15-7.30(m, 5H), 7.32(d, J=4.0Hz, 1H), 7.47(d, J=4.0Hz, 1H),7.64-7.90(m, 3H), 8.05(d, J=8.4Hz, 2H), 8.48(d, J=8.4Hz, 2H), 9.80(br s,1H), 12.85(br, 1H) 49 B-19 Bn

R 2.75(dd, J=9.6, 13.8Hz, 1H), 3.00(dd, J=4.8, 13.5Hz, 1H), 3.94(br s,1H), 6.11(s, 2H), 7.00(d, J=8.1Hz, 1H), 7.12-7.26(m, 9H), 8.71(br s,1H), 12.89(br s, 1H) 50 B-20 Bn

S 2.75(dd, J=9.3, 13.2Hz, 1H), 3.00(dd, J=5.1, 13.8Hz, 1H), 3.94(br s,1H), 6.11(s, 2H), 7.00(d, J=7.7Hz, 1H), 7.12-7.21(m, 9H), 8.71(br s,1H), 12.89(br s, 1H) 51 B-21 H

3.70(s, 2H), 6.11(s, 2H), 7.00(d, J=8.1Hz, 1H), 7.14(m, 1H), 7.16(s,1H), 7.38(d, J=3.9Hz, 1H), 7.54(d, J=3.9Hz, 1H), 8.47(s, 1H), 12.82(br,1H) 52 B-22 Me

R 1.22(d, J=7.2Hz, 3H), 3.88(m, 1H), 6.10(s, 2H), 7.00(d, J=8.1Hz, 1H),7.14(m, 1H), 7.16(s, 1H), 7.37(d, J=3.9Hz, 1H), 7.52(d, J=3.9Hz, 1H),8.60(m, 1H), 12.80(br, 1H)

[0154] TABLE 9 Example Compound No. No. R² R⁶ * ¹H-NMR (DMSO-d₆) 53 B-23i-Pr

R 0.82(d, J=6.6Hz, 3H), 0.86(d, J=6.9Hz, 3H), 2.00(m, 1H), 3.61(dd,J=6.3, 9.3Hz, 1H), 6.11(s, 2H), 7.00(d, J=7.8Hz, 1H), 7.14(m, 1H),7.16(s, 1H), 7.36(d, J=4.5Hz, 1H), 7.49(d, J=4.5Hz, 1H), 8.47(d,J=9.3Hz, 1H), 12.77(s, 1H) 54 B-24 i-Bu

R 0.78(d, J=6.6Hz, 3H), 0.85(d, J=6.6Hz, 3H), 1.44-1.45(m, 2H), 1.61(m,1H), 3.75(brs, 1H), 6.11(s, 2H), 7.00(d, J=8.1Hz, 1H), 7.14(m, 1H),7.36(d, J=3.9Hz, 1H), 7.49(d, J=3.9Hz, 1H), 8.60(brs, 1H), 12.78(br, 1H)55 B-25 MeS—CH₂—CH₂—

R 1.70-1.95(m, 2H), 1.98(s, 3H), 2.33-2.45(m, 2H), 3.94(m, 1H), 6.10(s,2H), 7.00(d, J=7.8Hz, 1H), 7.12(m, 1H), 7.16(s, 1H), 7.37(d, J=3.9Hz,1H), 7.50(d, J=3.9Hz, 1H), 8.63(d. J=9.0Hz, 1H), 12.90(brs, 1H) 56 B-26HOOC—CH₂—

R 2.47(dd, J=6.3, 16.2Hz, 1H), 2.68(dd, J=6.3, 16.2Hz, 1H), 4.17(m, 1H),6.10(s, 2H), 7.00(d, J=8.1Hz, 1H), 7.14(m, 2H), 7.36(d, J=3.9Hz, 1H),7.51(d, J=3.9Hz, 1H), 8.62(m, 1H), 12.70(br, 2H) 57 B-27 Indole- 3-yl)methyl

58 B-28 i-Pr

R 0.81(s, 3H), 0.86(s, 3H), 1.99(m, 1H), 3.60(m, 1H), 4.24-4.33(m, 4H),6.92(dd, J=0.3, 8.1Hz, 1H), 7.04-7.12(m, 2H), 7.35(d, J=3.9Hz, 1H),7.48(d, J=3.9Hz, 1H), 8.47(d, J=9.6Hz, 1H), 12.76(br s, 1H) 59 B-29 Bn

R 2.74(dd, J=9.6, 13.5Hz, 1H), 3.00(dd, J=4.8, 13.5Hz, 1H), 3.95(m, 1H),4.20-4.35(m, 4H), 6.93(d, J=8.1Hz, 1H), 7.04-7.30(m, 9H), 8.76(d,J=8.1Hz, 1H), 12.95(br s, 1H)

[0155] TABLE 10

Exam- ple Compound No. No. R² * ¹H-NMR (DMSO-d₆) 60 C-1 Bn R 2.76(dd,J=9.6, 13.5Hz, 1H), 3.00(dd, J=4.8, 13.5Hz, 1H), 3.97(brs, 1H),7.05-7.21(m, 5H), 7.64-7.67(m, 2H), 7.86(d, J=8.7Hz, 2H), 8.06(m, 1H),8.17-8.31(m, 5H), 8.59(d, J=6.6Hz, 1H), 8.85(s, 1H), 12.95(brs, 1H) 61C-2 Bn S 2.76(dd, J=9.3, 13.5Hz, 1H), 3.00(dd, J=5.4, 13.8Hz, 1H),3.98(brs, 1H), 7.10-7.21(m, 5H), 7.63-7.69(m, 2H), 7.86(d, J=9.0Hz, 2H),8.06(m, 1H), 8.16-8.31(m, 5H), 8.56(s, 1H), 8.85(s, 1H), 12.92(brs, 1H)

[0156] TABLE 11

Example Compound No. No. R² * ¹H-NMR (DMSO-d₆) 62 D-1 Bn R 2.74(dd,J=8.6, 13.5Hz, 1H), 2.95(dd, J=5.8, 13.5Hz, 1H), 3.89(m, 1H),7.10-7.30(m, 5H), 7.58(d, J=8.8Hz, 2H), 7.60-7.72(m, 2H), 7.91(d,J=8.8Hz, 2H), 7.99-8.22(m, 5H), 8.61(s, 1H), 10.73(s, 1H), 12.73(br, 1H)63 D-2 Bn S 2.74(dd, J=8.4, 13.5Hz, 1H), 2.95(dd, J=5.8, 13.5Hz, 1H),3.90(m, 1H), 7.10-7.30(m, 5H), 7.59(d, J=8.8Hz, 2H), 7.60-7.72(m, 2H),7.91(d, J=8.8Hz, 2H), 8.00-8.20(m, 5H), 8.61(s, 1H), 10.72(s, 1H),12.73(br, 1H)

[0157] TABLE 12

Example Compound No. No. R² * ¹H-NMR (DMSO-d₆) 64 E-1 Bn R 2.76(dd,J=9.3, 13.8Hz, 1H), 2.99(dd, J=5.4, 13.5Hz, 1H), 3.97(m, 1H),7.13-7.22(m, 5H), 7.66-7.75(m, 2H), 7.79(d, J=8.7Hz, 2H), 8.09(d,J=7.2Hz, 1H), 8.17(d, J=8.1Hz, 2H), 8.22-8.28(m, 3H), 8.54(d, J=9.6Hz,1H), 8.93(s, 1H), 12.82(br s, 1H) 65 E-2 Bn S 2.75(dd, J=9.6, 14.0Hz,1H), 3.00(dd, J=4.8, 13.2Hz, 1H), 3.96(m, 1H), 7.10-7.21(m, 5H),7.60-7.81(m, 5H), 8.07-8.28(m, 7H), 8.55(d, J=8.8Hz, 1H), 8.93(s, 1H),12.83(br s, 1H) 66 E-3 H 3.70(s, 2H), 7.66-7.77(m, 2H), 8.04(d, J=8.7Hz,2H), 8.09(d, J=7.8Hz, 1H), 8.18-8.36(m, 6H), 8.91(s, 1H), 12.71(br s,1H) 67 E-4 Me R 1.21(d, J=6.9Hz, 3H), 3.88(m, 1H), 7.66-7.77(m, 2H),8.00-8.06(m, 2H), 8.09(d, J=7.8Hz, 1H), 8.18-8.27(m, 3H), 8.29-8.34(m,2H), 8.39(d, J=7.8Hz, 1H), 8.92(s, 1H), 12.61(br s, 1H) 68 E-5 Me S1.21(d, J=6.6Hz, 3H), 3.88(m, 1H), 7.66-7.77(m, 2H), 8.03(d, J=8.7Hz,2H), 8.08(d, J=7.2Hz, 1H), 8.18-8.27(m, 3H), 8.32(d, J=8.7Hz, 2H),8.39(d, J=7.5Hz, 1H), 8.91(s, 1H), 12.68(br s, 1H) 69 E-6 i-Pr R 0.82(d,J=6.6H, 3H), 0.86(d, J=6.9Hz, 3H), 1.99(m, 1H), 3.61(m, 1H),7.66-7.77(m, 2H), 8.02(d, J=8.7Hz, 2H), 8.09(d, J=7.5Hz, 1H),8.18-8.33(m, 6H), 8.92(s, 1H), 12.67(br s, 1H) 70 E-7 i-Pr S 0.82(d,J=6.6H, 3H), 0.86(d, J=6.9Hz, 3H), 1.98(m, 1H), 3.61(t, J=6.9Hz, 1H),7.66-7.77(m, 2H), 8.00-8.05(m, 2H), 8.09(d, J=7.8Hz, 1H), 8.18-8.33(m,6H), 8.92(s, 1H), 12.67(br s, 1H)

[0158] TABLE 13 Example Compound No. No. R² * ¹H-NMR (DMSO-d₆) 71 E-8i-Bu R 0.75 (d, J = 6.3 Hz, 3H), 0.84 (d, J = 6.6 Hz, 3H), 1.35-1.52 (m,2H), 1.60 (m, 1H), 3.75 (m, 1H), 7.66-7.77 (m, 2H), 8.02 (d, J = 8.4 Hz,2H), 8.09 (d, J = 8.1 Hz, 1H), 8.18-8.27 (m, 3H), 8.31 (d, J = 8.4 Hz,2H), 8.38 (d, J = 8.4 Hz, 1H), 8.92 (s, 1H), 12.64 (br s, 1H) 72 E-9i-Bu S 0.75 (d, J = 6.3 Hz, 3H), 0.84 (d, J = 6.6 Hz, 3H), 1.35-1.52 (m,2H), 1.61 (m, 1H), 3.76 (m, 1H), 7.66-7.77 (m, 2H), 8.02 (d, J = 8.4 Hz,2H), 8.09 (d, J = 7.2 Hz, 1H), 8.18-8.28 (m, 3H), 8.31 (d, J = 8.4 Hz,2H), 8.38 (d, J = 7.8 Hz, 1H), 8.92 (s, 1H), 12.63 (br s, 1H) 73  E-10(Indole- R 2.90 (dd, J = 8.4, 14.4 Hz, 1H), 3.11 (d, 3- J = 5.7, 14.4Hz, 1H), 4.00 (dt, yl)methyl J = 8.4, 5.7 Hz, 1H), 6.88-7.00 (m, 2H),7.09 (d, J = 2.4 Hz, 1H), 7.21 (d, J = 7.5 Hz, 1H), 7.35 (d, J = 7.2 Hz,1H), 7.67-7.77 (m, 4H), 8.05 (d, J = 8.7 Hz, 2H), 8.09 (d, J = 7.8 Hz,1H), 8.19-8.29 (m, 3H), 8.47 (d, J = 8.4 Hz, 1H), 8.93 (s, 1H), 10.77(d, J = 1.2 Hz, 1H), 12.72 (br s, 1H)

[0159] TABLE 14

Example Compound No. No. R² * ¹H-NMR (DMSO-d₆) 74 F-1 Bn R 2.76(dd,J=9.9, 13.8Hz, 1H), 3.00(d, J=5.1, 13.8Hz, 1H), 3.99(m, 1H),7.10-7.22(m, 5H), 7.62-7.71(m, 2H), 7.82(d, J=8.4Hz, 2H), 8.05(m, 1H),8.12-8.22(m, 3H), 8.25(d, J=8.4Hz, 2H), 8.61(d, J=8.4Hz, 1H), 8.77(s,1H), 12.84(br s, 1H) 75 F-2 Bn S 2.76(dd, J=9.6, 13.8Hz, 1H), 3.00(d,J=5.1, 13.8Hz, 1H), 3.99(m, 1H), 7.10-7.23(m, 5H), 7.62-7.71(m, 2H),7.82(d, J=8.4Hz, 2H), 8.05(m, 1H), 8.12-8.22(m, 3H), 8.25(d, J=8.4Hz,2H), 8.62(d, J=9.3Hz, 1H), 8.77(s, 1H), 12.85(br s, 1H)

[0160] TABLE 15

Example Compound No. No. R² * ¹H-NMR (DMSO-d₆) 76 G-1 i-Pr R 0.82(d,J=6.9Hz, 3H), 0.86(d, J=6.9Hz, 3H), 1.99(m, 1H), 3.61(m, 1H), 7.69(m,2H), 8.00-8.10(m, 3H), 8.10-8.40(m, 6H), 8.82(s, 1H), 12.67(br s, 1H)

Test Example 1 Isolation and Purification of MMP

[0161] MMP-1 was purchased from Yagai.

[0162] MMP-2 was purchased from Calbiochem-Novabiochem International,Inc.

[0163] In regard to MMP-8, catalytic domain (⁹⁹Phe˜²⁶²Gly) was amplifiedwith PCR using commercial available Human Bone Marrow cDNA. This wascloned in Escherichia. coli expression vector pTrc99AHE inserted withHis-tag sequence and enterokinase digestion-site, induced and expressedby IPTG (Isopropyl-β-D-thiogalactopyranoside) and expressed in ainsoluble fraction (Than F. Ho, M. Walid Qoronfleh, Robert C. Wahl,Trica A. Pulvino, Karen J. Vavra, Joe Falvo, Tracey M. Banks, PatriciaG. Brake and Richard B. Ciccarelli: Gene expression, purification andcharacterization of recombinant human neutrophil collagenase. Gene 146,(1994) 297-301, Prepared by the a improved method of this material).Isolation of MMP-8 from insoluble fraction was carried out by dissolvingin modifier (6M urea) by a usual method and purification with metalchelate chromatography. And then removing modifier (6M urea) withdialysis and refolding of the enzyme spontaneously gave activated MMP-8.

[0164] MMP-9 was isolated and purified by using a combination ofprocedures described in previous reports as follows. Yasunori Okada,Yukio Gonoji, Katsumi Naka, Katsuro Tomita, Isao Nakanishi, KazushiIwata, Kyoko Yamashita, and Taro Hayakawa: Matrix metalloproteinase 9(92-kDa gelatinase/type IV collagenase) from HT1080 human fibrosarcomacells. Purification and activation of the precursor and enzymicproperties. J. Biol. Chem., 267 (1.992) 21712-21719. Yasunori Okada,Tatsuhisa Morodomi, Jan J, Enghild, Ko Suzuki, Atsushi Yasui, IsaoNakanishi, Guy Salvesen and Hideaki Nagase: Matrix metalloproteinase 2from human rheumatoid synovial fibroblasts. Purification and activationof the precursor and enzymic properties. Eur. J. Biochem. 194 (1990)721-730. Robin V Ward, Rosalind M Hembry, John J Reynolds and GillianMurphy: The purification of tissue inhibitor of metalloproteinase-2 fromits 72 kDa progelatinase complex. Biochem. J. 278 (1991) 179-187.

[0165] Briefly, human fibrosarcoma ATCC HT1080 cell line was cultured toconfluent in Dulbecco's Modified Medium (DMEM) containing 10% fetal-calfserum at 37° C. for 48 hours. Subsequently, the medium of confluentculture was changed to serum-free DMEM medium. To obtain MMP-9,Phorbol-12-myristate-13-acetate (TPA) must be added to this serum-freeDMEM medium at a concentration of 50 ng/ml. The TPA treated medium wascentrifuged at 3000 rpm for 15 min and the supernatant was concentratedto 450 ml by a Toyo-Roshi UP-20 apparatus with an ultrafiltrationmembrane. Then, proMMP-9 in this concentrated solution was purified byusing columns of Gelatin-Sepharose and Concanavalin A-Sepharose. Thepool containing proMMP-9 was dialyzed, concentrated (Toyo-Roshi UP-20)and applied to columns of Sephacryl S-200 and Green A matrix for theseparation from TIMPs. The obtained proMMP-9 fraction was activated byTPCK-Trypsin (final conc. 3 μg/μl reaction mix.).

[0166] In regard to MMP-12, catalytic domain(¹⁰⁰Phe˜²⁶³Gly) wasamplified with RT-PCR from Human Placenta Total RNA. This was cloned inEscherichia coli expression vector pTrc99AHE inserted with His-tagsequence and enterokinase digestion-site, induced and expressed by IPTG(Isopropyl-β-D-thiogalactopyranoside) and expressed in a insolublefraction. Isolation of MMP-12 from a insoluble fraction was carried outby dissolving in modifier (6M urea) by a usual method and purificationwith metal chelate chromatography (Ni Chelateing Sepharose). And thenremoving modifier (6M urea) with dialysis and refolding of the enzymespontaneously gave activated MMP-12.

[0167] In regard to MMP-13, mRNA was prepared from carcinoma cell SW1353derived from human cartilage stimulate by IL-1, TNF and catalytic domain(¹⁰⁴Tyr˜²⁶⁷Gly) was amplified with RT-PCR. This was cloned inEscherichia coli expression vector pTrc99AHE inserted with His-tagsequence and enterokinase digestion-site, induced and expressed by IPTG(Isopropyl-β-D-thiogalactopyranoside) and expressed in a insolublefraction. Isolation of MMP-1.3 from a insoluble fraction was carried outby dissolving in modifier (6M urea) by a usual method and purificationwith metal chelate chromatography (Ni Chelateing Sepharose). And thenremoving modifier (6M urea) with dialyze and refolding of the enzymespontaneously gave activated MMP-13.

Test Example 2 Assay for Inhibitory Activities on Various Type of MMPs

[0168] The enzymatic activity on MMPs was analyzed by the methoddescribed in “C. Graham Knight, Frances Willenbrock and Gillian Murphy:A novel coumarin-labelled peptide for sensitive continuous assays of thematrix metalloproteinases: FEBS LETT., 296, (1992), 263-266”. Thesubstrate: MOCAc-Pro-Leu-Gly-Leu-A₂Pr(DNP)-Ala-Arg-NH₂ was purchasedfrom Peptide Institute, Inc., Osaka, Japan. The measurement of theinhibitory activities (IC₅₀) was carried out by the following fourmethods;

[0169] (A) Reaction with substrate, enzyme (MMPs) and inhibitor

[0170] (B) Reaction with substrate and inhibitor, without enzyme

[0171] (C) Reaction with substrate and enzyme (MMPs), without inhibitor

[0172] (D) Reaction with substrate only

[0173] IC₅₀ values were calculated by using the following formula andeach fluorescence values of above four methods (A to D).

% inhibition={1−(A−B)/(C−D)}×100

[0174] IC₅₀ means the concentration required to inhibit 50% of theenzyme activity.

[0175] The results are shown in Table 16. TABLE 16 Compound MMP-1 MMP-2MMP-8 MMP-9 MMP-12 MMP-13 No. (μM) (μM) (μM) (μM) (μM) (μM) A-1 >10 0.400.57 0.77 0.0076 0.30 A-2 >10 >10 >10 >10 0.016 >10 A-3 >10 >10 >10 >100.021 >10 A-5 >10 0.11 1.06 0.33 0.014 0.34 A-6 >10 0.40 0.57 0.770.0076 0.30 A-8 >10 0.57 2.44 3.28 0.016 2.77 A-9 >10 0.25 >10 1.800.069 2.88 A-10 >10 0.37 4.38 1.44 0.058 1.55 A-11 >10 0.37 0.58 1.270.0059 0.46 A-12 >10 0.37 3.63 1.79 0.035 1.14 A-15 >10 0.46 >10 0.900.032 0.89 A-16 >10 0.11 1.32 0.62 0.010 0.37 A-17 >10 0.39 0.60 1.060.0078 0.37 A-22 >10 0.013 0.010 0.30 0.0079 0.037 B-1 >10 0.82 >10 >100.042 >10 B-2 >10 >10 >10 >10 0.24 >10 B-3 >10 0.18 1.40 0.75 0.016 >10B-4 >10 0.24 0.54 0.53 0.011 0.64 B-5 >10 2.23 2.34 3.27 0.082 6.90B-6 >10 0.35 2.09 0.84 0.023 0.84 B-7 >10 2.03 7.79 6.31 0.16 >10B-8 >10 1.12 2.65 2.11 0.048 2.30 B-9 >10 1.27 >10 4.23 0.26 7.18B-10 >10 0.35 1.00 0.87 0.0088 0.95 B-11 >10 1.86 2.89 4.9 0.11 6.14B-12 >10 1.25 2.60 1.10 0.040 1.40 B-17 >10 >10 >10 >10 0.82 >10 C-1 >100.14 >10 >10 0.055 0.45 C-2 >10 >10 >10 >10 0.14 >10 D-2 >10 0.56 4.516.56 0.15 2.33

Test Example 3

[0176] Sprague-Dawley male rats (390-430 g initial body weight) wereexposed daily to smoke from commercial filtered cigarettes (30cigarettes/rat/day, 5 days/week, for 7 to 8 weeks) with asmoke-generating and whole-body exposure system. The animals received 30mg/kg p.o. twice daily of compound (B-6), which was suspended with 0.5%methyl cellulose. Vehicle animals received 2 ml/kg of 0.5% methylcellulose. At 16-24 hr after the last exposure with cigarette smoke,anesthesia was induced with intraperitoneal injection of 40 mg/kg ofpentobarbital sodium. Immediately after muscle relaxation withintravenous pancuronium bromide (0.3 mg/rat), animals were mechanicallyventilated with a pressure-limited ventilator and were evaluated dynamiccompliance. After exsanguination, the lung was attached to a glasssyringe via a connector tube and continuously inflated through theairway to a transpulmonary pressure of 30 cmH₂O, deflated them to a Ptpof 0 cmH₂O, and aspirated them to a Ptp of −20 cmH₂O. The change of Ptpand lung volume was monitored and recorded as the deflationpressure-volume (P-V) curve. Static lung compliance defined as the slopeof steep portion of the deflation P-V curve was evaluated. Inspiratorycapacity (IC) defined as the difference in lung volume between totallung capacity at a Ptp of 25 cmH₂O and functional residual capacity at aPtp of 0 cmH₂O was evaluated.

[0177] Data are expressed as means ±S.D. Statistical analysis wasperformed with one-sided Student's t-test. A value of P<0.05 wasconsidered significant.

[0178] The results were shown in Table 17. TABLE 17 dynamic complianceStatic lung compliance Inspiratory capacity (ml/cmH₂O/kg) (ml/cmH₂O/kg)(ml/kg) n = Air exposure 0.84 ± 0.12 2.06 ± 0.16 21.77 ± 1.63 8Cigarette smoke exposure 1.02 ± 0.14 # 2.36 ± 0.38 # 23.74 ± 2.64 # 7(Vehicle) Compound (B-6) 0.96 ± 0.17 2.05 ± 0.25 * 21.76 ± 1.85 7Administration

[0179] As shown in Table 17, compound (B-6) significantly reduced theincrease of static lung compliance and tended to attenuate the increaseof dynamic compliance and inspiratory capacity by cigarette smokeexposure in the rats.

Formulation Example Formulation Example 1

[0180] Granules are prepared using the following ingredients.Ingredients The compound represented  10 mg by the formula(I) Lactose700 mg Corn starch 274 mg HPC-L  16 mg 1000 mg 

[0181] The compound represented by the formula (I) and lactose are madepass through a 60 mesh sieve. Corn starch is made pass through a 120mesh sieve. They are mixed by a twin shell blender. An aqueous solutionof HPC-L (low mucosity hydroxypropylcellulose) is added to the mixtureand the resulting mixture is kneaded, granulated (by the extrusion withpore size 0.5 to 1 mm mesh), and dried. The dried granules thus obtainedare sieved by a swing sieve (12/60 mesh) to yield the granules.

Formulation 2

[0182] Powders for filling capsules are prepared using the followingingredients. Ingredients The compound represented by 10 mg the formula(I) Lactose 79 mg Corn starch 10 mg Magnesium stearate  1 mg 100 mg 

[0183] The compound represented by the formula (I) and lactose are madepass through a 60 mesh sieve. Corn starch is made pass through a 120mesh sieve. These ingredients and magnesium stearate are mixed by a twinshell blender. 100 mg of the 10-fold trituration is filled into a No. 5hard gelatin capsule.

Formulation 3

[0184] Granules for filling capsules are prepared using the followingingredients. Ingredients The compound represented by 15 mg the formula(I) Lactose 90 mg Corn starch 42 mg HPC-L  3 mg 150 mg 

[0185] The compound represented by the formula (I) and lactose are madepass through a 60 mesh sieve. Corn starch is made pass through a 120mesh sieve. After mixing them, an aqueous solution of HPC-L is added tothe mixture and the resulting mixture is kneaded, granulated, and dried.After the dried granules are lubricated, 150 mg of that are filled intoa No. 4 hard gelatin capsule.

Formulation 4

[0186] Tablets are prepared using the following ingredients. IngredientsThe compound represented by 10 mg the formula (I) Lactose 90 mgMicrocrystal cellulose 30 mg CMC-Na 15 mg Magnesium stearate  5 mg 150mg 

[0187] The compound represented by the formula (I), lactose,microcrystal cellulose, and CMC-Na (carboxymethylcellulose sodium salt)are made pass through a 60 mesh sieve and then mixed. The resultingmixture is mixed with magnesium stearate to obtain the mixed powder forthe tablet formulation. The mixed powder is compressed to yield tabletsof 150 mg.

[0188] Industrial Applicability

[0189] The sulfonamide derivatives of the present invention haveinhibiting activities against the metalloproteinase, especiallyselectively inhibiting activities agaist MMP-12 and are useful as thetreating or preventing agent of chronic obstructive pulmonary disease.

1. A compound of the formula (I):

wherein R¹ is NHOH, hydroxy, or lower alkyloxy; R² is hydrogen atom, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R³ is hydrogen atom, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R⁴ is optionally substituted arylene, or optionally substituted heteroarylene; R⁵ is a bond, —(CH₂)p—, —CH═CH—, —C≡C—, —CO—, CO—NH—, —N═N—, —N(R^(A))—, —NH—CO—NH—, —NH—CO—, —O—, —S—, —SO₂—, —SO₂NH—, —SO₂—NH—N═CH—, or a group represented by the formula:

wherein R^(A) is hydrogen atom or lower alkyl, p is 1 or 2 R⁶ is optionally substituted naphtyl, optionally substituted isoquinolyl, optionally substituted quinolyl, optionally substituted 1,3-benzodioxolyl, optionally substituted benzofuranyl, or optionally substituted benzothienyl, its optically active substance, its prodrug, their pharmaceutically acceptable salt, or solvate thereof.
 2. A compound of the formula (II):

wherein R¹, R², R³, R⁴ and R⁵ are as defined in claim 1; R⁷ is each independently hydrogen atom, halogen, lower alkyl, cycloalkyl, lower alkenyl, lower alkynyl, lower alkyloxy, lower alkenyloxy, lower alkylthio, halo(lower)alkyl, hydroxy, carboxy, lower alkyloxycarbonyl, aminocarbonyl, acyl, nitro, cyano, or optionally substituted amino; m is 0, 1, 2, or 3, its optically active substance, its prodrug, their pharmaceutically acceptable salt, or solvate thereof.
 3. A compound of the formula (III):

wherein R¹, R³, R⁴, and R⁵ are as defined in claim 1; R⁷ and m are as defined in claim 2; R⁸ is hydrogen atom, lower alkyl optionally substituted with aminocarbonyl or lower alkylthio, aryl optionally substituted with hydroxy, aralkyl optionally substituted with hydroxy, or heteroarylalkyl optionally substituted with hydroxy, its optically active substance, its prodrug, their pharmaceutically acceptable salt, or solvate thereof.
 4. A compound, its optically active substance, its prodrug, their pharmaceutically acceptable salt, or solvate thereof as claimed in any one of claims 1 to 3, wherein R¹ is hydroxy.
 5. A compound, its optically active substance, its prodrug, their pharmaceutically acceptable salt, or solvate thereof as claimed in any one of claims 1 to 4, wherein R² and R⁸ are each independently hydrogen atom, lower alkyl optionally substituted with aminocarbonyl or lower alkylthio, phenyl optionally substituted with hydroxy, benzyl optionally substituted with hydroxy, or indol-3-ylmethyl optionally substituted with hydroxy.
 6. A compound, its optically active substance, its prodrug, their pharmaceutically acceptable salt, or solvate thereof as claimed in any one of claims 1 to 5, wherein R² and R⁸ are each independently hydrogen atom, methyl, isopropyl, isobutyl, aminocarbonylmethyl, 2-methylthioethyl, 4-hydroxyphenyl, benzyl, 4-hydroxybenzyl, indol-3-ylmethyl, or (5-hydroxy-indol-3-yl)methyl.
 7. A compound, its optically active substance, its prodrug, their pharmaceutically acceptable salt, or solvate thereof as claimed in any one of claims 1 to 6, wherein R³ is hydrogen atom.
 8. A compound, its optically active substance, its prodrug, their pharmaceutically acceptable salt, or solvate thereof as claimed in any one of claims 1 to 7, wherein R⁴ is 1,4-phenylene or 2,5-thiophen-diyl.
 9. A compound, its optically active substance, its prodrug, their pharmaceutically acceptable salt, or solvate thereof as claimed in any one of claims 1 to 8, wherein R⁵ is —C≡C—, —CO—NH—, —NH—CO—, —O—, or a group represented by a formula:


10. A compound of the formula (IV):

wherein R⁹ is hydrogen atom, methyl, isopropyl, isobutyl, aminocarbonylmethyl, 2-methylthioethyl, 4-hydroxyphenyl, benzyl, 4-hydroxybenzyl, indol-3-ylmethyl, or (5-hydroxy-indol-3-yl)methyl; R¹⁰ is 1,4-phenylene or 2,5-thiophen-diyl; R¹¹ is —C≡C—, —CO—NH—, —NH—CO—, —O—, or a group represented by a formula:

R¹² is each independently hydrogen atom, halogen, lower alkyl, lower alkyloxy, halo(lower)alkyl, nitro, cyano, optionally substituted amino, or hydroxy; m is 0, 1, 2, or 3, its optically active substance, its prodrug, their pharmaceutically acceptable salt, or solvate thereof.
 11. A pharmaceutical composition containing a compound of any one of claims 1 to 10 as an active ingredient.
 12. A composition for inhibiting metalloproteinase containing a compound of any one of claims 1 to 10 as an active ingredient.
 13. A composition for inhibiting matrix metalloproteinase containing a compound of any one of claims 1 to 10 as an active ingredient.
 14. A composition for inhibiting matrix metalloproteinase-12 containing a compound of any one of claims 1 to 10 as an active ingredient.
 15. A composition for treating or preventing chronic obstructive pulmonary disease which contains as an active ingredient a compound of any one of claims 1 to
 10. 16. Use of a compound of any one of claims 1 to 10 for preparation of a pharmaceutical composition for treating chronic obstructive pulmonary disease.
 17. A method for treating a mammal, including a human, to alleviate the pathological effects of chronic obstructive pulmonary disease, which comprises administration to said mammal of a compound as claimed in any one of claims 1 to 10 in a pharmaceutically effective amount.
 18. A method of inhibiting MMP-12, which is characterized by contacting a compound as claimed in any one of claims 1 to 10 with MMP-12.
 19. A pharmaceutical composition containing as an active ingredient a compound having an inhibitory activity against matrix metalloproteinase-12.
 20. A composition for treating or preventing chronic obstructive pulmonary disease containing as an active ingredient a compound having an inhibitory activity against matrix metalloproteinase-12.
 21. A method for treating a mammal, including a human, to alleviate the pathological effects of chronic obstructive pulmonary disease, which comprises administration to said mammal of a compound having an inhibitory activity against matrix metalloproteinase-12.
 22. Use of a compound having an inhibitory activity against matrix metalloproteinase-12 for preparation of a pharmaceutical composition for treating chronic obstructive pulmonary disease.
 23. A method of inhibiting matrix metalloproteinase-12, which is characterized by contacting a compound having an inhibitory activity against matrix metalloproteinase-12 with matrix metalloproteinase-12.
 24. (Addition) A compound of the formula (II):

wherein R¹ is NHOH, hydroxy, or lower alkyloxy; R² is optionally substituted lower alkyl, (hydroxy, carboxy, lower alkylthio, or aminocarbonyl as a substituent), optionally substituted aryl, optionally substituted aralkyl; R³ is hydrogen atom, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R⁴ is 1,4-phenylene or 2,5-thiophen-diyl; R⁵ is —C≡C—, —CO—NH—, —NH—CO—, —O—, or a group represented by a formula:

R⁷ is each independently hydrogen atom, halogen, lower alkyl, cycloalkyl, lower alkenyl, lower alkynyl, lower alkyloxy, lower alkenyloxy, lower alkylthio, halo(lower)alkyl, hydroxy, carboxy, lower alkyloxycarbonyl, aminocarbonyl, acyl, nitro, cyano, or optionally substituted amino; m is 0, 1, 2, or 3 its optically active substance, its prodrug, their pharmaceutically acceptable salt, or solvate thereof.
 25. (Addition) A compound of the formula (IV):

wherein R⁹ is methyl, isopropyl, isobutyl, aminocarbonylmethyl, 2-methylthioethyl, 4-hydroxyphenyl, benzyl, 4-hydroxybenzyl; R¹⁰ is ,4-phenylene or 2,5-thiophen-diyl; R¹¹ is —C≡C—, —CO—NH—, —NH—CO—, —O—, or a group represented by a formula:

R¹² is each independently hydrogen atom, halogen, lower alkyl, lower alkyloxy, halo(lower)alkyl, nitro, cyano, optionally substituted amino, or hydroxy; m is 0, 1, 2, or 3 its optically active substance, its prodrug, their pharmaceutically acceptable salt, or solvate thereof.
 26. (Addition) A pharmaceutical composition containing a compound as claimed in claims 24 or 25 as an active ingredient.
 27. (Addition) A composition for inhibiting metalloproteinase containing a compound as claimed in claims 24 or 25 as an active ingredient.
 28. (Addition) A composition for inhibiting matrix metalloproteinase containing a compound as claimed in claims 24 or 25 as an active ingredient.
 29. (Addition) A composition for inhibiting matrix metalloproteinase-12 containing a compound as claimed in claims 24 or 25 as an active ingredient.
 30. (Addition) A composition for treating or preventing chronic obstructive pulmonary disease which contains as an active ingredient a compound as claimed in claims 24 or
 25. 31. (Addition) Use of a compound as claimed in claims 24 or 25 for preparation of a pharmaceutical composition for treating chronic obstructive pulmonary disease.
 32. (Addition) A method for treating a mammal, including a human, to alleviate the pathological effects of chronic obstructive pulmonary disease, which comprises administration to said mammal of a compound as claimed in claims 24 or 25 in a pharmaceutically effective amount.
 33. (Addition) A method of inhibiting MMP-12, which is characterized by contacting a compound as claimed in claims 24 or 25 with MMP-12. 